Predicted condensation-related signatures localize to two C-terminal regions of the prion protein across cervid PRNP variants associated with chronic wasting disease
- 1University of Maryland School of Pharmacy
Abstract
Genetic variation in cervid PRNP influences chronic wasting disease (CWD) susceptibility and progression, but it remains unclear whether disease-associated substitutions produce localized differences in sequence-derived properties relevant to prion protein (PrPC) condensation. We compared a white-tailed deer (WTD) reference sequence with 10 modeled variants on the same mature PrP scaffold (residues 24-233). For each sequence, we calculated intrinsic disorder, FuzDrop per-residue droplet-promoting propensity (pDP) and binding-mode entropy (Sbind), predicted residue-level pKa values, and a discrete-charge summary at pH 7.0. The overall profiles preserve a long N-terminal droplet-promoting region, whereas variant-associated differences are concentrated in selected intervals. In the FuzDrop outputs, residues 126-140 show allele-dependent changes in pDP near the droplet-promoting threshold, and residues 220-230 show variant-specific changes in Sbind, including lower Sbind for S225F/Y and higher Sbind for elk-like Q226E. These differences occur without large changes in overall intrinsic disorder. KaML pKa predictions identify near-neutral titratable sites that provide electrostatic context for these local predictor differences. Independent atomistic simulations of monomeric PrP further detected variant-sensitive backbone behavior and intramolecular contacts involving these intervals. Together, the analysis identifies residues 126-140 and 220-230 as computationally defined candidate intervals that overlap regions implicated independently in prion conversion or CWD fibril structure, motivating direct tests of cervid PrP condensation and maturation.
Related
- Single-cell RNA sequencing of terminal ileal biopsies identifies signatures of Crohn’s disease pathogenesis
- NPlasmid-seq: Cas9-encoded terminal signatures enable molecule-level nanopore quality control of vector and IVT-template plasmids
- Gut bacterial composition and predicted functional profiles associated with depressive symptom burden in Japanese adults recruited independently of depression diagnosis
- ASC specks and α-synuclein amplify microglial NLRP3 inflammasome activation and co-localize with Lewy body pathology
- The population frequency of predicted pathogenic variants in the genes associated with Autosomal Dominant Polycystic Liver Disease (ADPLD) and kidney cysts
BibTeX
@misc{dayhoff2026predicted,
title = {{Predicted condensation-related signatures localize to two C-terminal regions of the prion protein across cervid PRNP variants associated with chronic wasting disease}},
author = {G. W. Dayhoff and L. Dorosh and H. Wille and V. N. Uversky and M. Stepanova},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762346},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762346v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Predicted condensation-related signatures localize to two C-terminal regions of the prion protein across cervid PRNP variants associated with chronic wasting disease
AU - G. W. Dayhoff
AU - L. Dorosh
AU - H. Wille
AU - V. N. Uversky
AU - M. Stepanova
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762346
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762346v1
AB - Genetic variation in cervid PRNP influences chronic wasting disease (CWD) susceptibility and progression, but it remains unclear whether disease-associated substitutions produce localized differences in sequence-derived properties relevant to prion protein (PrPC) condensation. We compared a white-tailed deer (WTD) reference sequence with 10 modeled variants on the same mature PrP scaffold (residues 24-233). For each sequence, we calculated intrinsic disorder, FuzDrop per-residue droplet-promoting propensity (pDP) and binding-mode entropy (Sbind), predicted residue-level pKa values, and a discrete-charge summary at pH 7.0. The overall profiles preserve a long N-terminal droplet-promoting region, whereas variant-associated differences are concentrated in selected intervals. In the FuzDrop outputs, residues 126-140 show allele-dependent changes in pDP near the droplet-promoting threshold, and residues 220-230 show variant-specific changes in Sbind, including lower Sbind for S225F/Y and higher Sbind for elk-like Q226E. These differences occur without large changes in overall intrinsic disorder. KaML pKa predictions identify near-neutral titratable sites that provide electrostatic context for these local predictor differences. Independent atomistic simulations of monomeric PrP further detected variant-sensitive backbone behavior and intramolecular contacts involving these intervals. Together, the analysis identifies residues 126-140 and 220-230 as computationally defined candidate intervals that overlap regions implicated independently in prion conversion or CWD fibril structure, motivating direct tests of cervid PrP condensation and maturation.
ER -